Background/Purpose: DLE is a chronic, scarring inflammatory autoimmune disease of the skin. The precise molecular pathways underlying DLE pathogenesis have not been fully delineated. To obtain a more complete view of the pathologic processes involved in DLE, we undertook a comprehensive analysis of gene expression profiles from DLE affected skin.

Methods: Microarray gene expression data was obtained from skin biopsy samples of three studies (GSE81071, GSE72535, & GSE52471). Differentially expressed genes (DEGs) between DLE and control were identified by LIMMA analysis. Weighted gene co-expression network analysis (WGCNA) yielded modules of co-expressed genes. Modules correlating to clinical data were prioritized. Correlated modules were interrogated for statistical enrichment of immune and non-immune cell type specific gene signatures. Genes were functionally characterized using a curated immune-specific gene functional category database (BIG-C) and pathways elucidated using IPA^®. Queries of a perturbation database (LINCS, Library of Integrated Network-Based Cellular Signatures) were used to identify drugs that could reverse the altered gene expression patterns in DLE.

Results: For each dataset, between 7-12 WGCNA modules had significant correlations to disease. Significant WGCNA module preservation was observed between all three datasets. Non-immune cell types (fibroblasts, keratinocytes, melanocytes) and also Langerhans cells are represented in WGCNA modules negatively correlated with disease. An immune cell signature was noted in WGCNA modules positively correlated to DLE, including DCs, myeloid cells, CD4⁺ & CD8⁺ T cells, NK cells, B cells as well as pre- and post-switch plasma cells (PCs). The presence of both Ig -κ & -λ as well as multiple VL genes suggests the presence of polyclonal PCs. Chemokines that mediate lymphocyte organization and/or recruitment into the skin were identified, including CCL5,7,8 & CXCL9-10,13. Cytokines (TNF, IFNγ, IFNα, IL1β, IL2, IL6, IL12, IL17, IL23 & IL27), signaling molecules (CD40L, PI3K, & mTOR) and transcription factors (NF-κB, NF-AT), as well as cellular proliferation, were evident. IPA^® UPR analysis indicated that many of the expressed genes could be secondary to signaling by TNF, IFNγ, IFNα, CD40L, IL1β, IL2, IL6, IL12, IL17, IL23 & IL27. Interestingly, connectivity analysis using LINCS/CLUE identified high priority drug targets, such as IKZF1/3 (lenalidomide, CC-220), JAK1/2 (ruxolitinib) and HDAC6 (Ricolinostat) may prove to be options for therapeutic intervention.

Conclusion: Bioinformatic analysis of DLE gene expression has elucidated many dysregulated signaling pathways potentially involved in the pathogenesis of DLE that could be targeted by novel therapeutic strategies. Further investigation of these signatures may enhance our understanding of the pathogenesis of DLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/analysis-of-discoid-lupus-erythematosus-dle-gene-expression-reveals-dysregulation-of-pathogenic-pathways-associated-with-infiltrating-immune-inflammatory-cells/